This application requests funding for a state-of-the-art console upgrade and cryogenic probe for an 18 year-old 500 MHz instrument for solution state NMR spectroscopy at the Boston University School of Medicine which is no longer supported by its manufacturer. The upgrade will increase the sensitivity of the NMR spectrometer by over an order of magnitude. The requested console is equipped with four channels, which allows running any currently available solution NMR experiments, a number of which cannot be run on any of the existing spectrometers at Boston University. Access to high-field NMR spectrometers has always been limited both nationwide and specifically in the Boston area, which restricts the ability of scientists to tackle a number of challenging areas of biomedical research. The upgraded 500 MHz spectrometer will allow faster data collection, with higher quality, particularly for larger proteins. This will drastically increase the capacity of the NMR facility. It will also enable users to study the structure and dynamics of proteins and complexes with high molecular weights and/or limited solubility, which are not possible on the current instrument due to its lack of sensitivity. The research of the nine major users includes the following NIH-funded projects that will directly benefit from a state-of-the-art 500 MHz NMR spectrometer: 1) Structure and dynamics and folding of proteins of the cardiovascular system. 2) Structural biology and dynamics of fatty acid transport proteins. 3) Mechanistic studies of normal and pathogenic Notch signaling. 4) Molecular mechanisms of translation initiation. 5) Nucleolar targeting and a type IVb protein secretion system. 6) Plasma lipoproteins and apolipoproteins: Structure and Biology. 7) Structure and function of transcription factors. 8) Structural studies of neurotoxic prion proteins. 9) Metabolomics of periodontal disease. Use of the upgraded 500 MHz NMR spectrometer by other researchers will be encouraged and instrument time will be made available for them. In summary, the requested upgrade and cryogenic probe for a 500 MHz NMR spectrometer will be a valuable asset for the biomedical research community at Boston University and the Boston area. It will immediately impact active NIH-funded research in multiple areas, in particular cardiovascular disease, fatty acid transport, gene expression, protein biogenesis, infectious disease and signal transduction.